Peptide Ligands for the Parathyroid Hormone Receptor and Translational Applications
Thomas Gardella
Associate Professor of Medicine & Biochemistry, Harvard Medical School
The parathyroid hormone receptor (PTHR1) is a class B GPCR that plays key roles in calcium homeostasis and bone development, via binding the endogenous peptide ligands, PTH and PTH-related protein, respectively. The PTHR1 is a key therapeutic target, and PTH(1-34) and a PTHrP(1-34) analog peptide are currently successful treatment options for osteoporosis. PTH ligand efficacy in vivo is critically dependent on duration of action on the PTHR1, and we have identified PTH peptide analogs that mediate signaling responses ranging from very transient to very prolonged, in part via selective binding to the receptor in a G protein-coupled conformation (RG, transient) versus a G protein-independent conformation (R0, prolonged). One long-acting PTH analog, shown to induce sustained calcemic responses when injected into animals, is now in clinical trials as a potential hormone-replacement therapy for hypoparathyroidism. Also identified are PTH(7-36) peptide analogs that act as inverse agonists on constitutively active PTHR1 mutants that cause Jansen’s chondrodysplasia, and one of these is being pursued as a potential therapy for this rare disease. The PTHR1 thus offers a rich molecular landscape for the discovery of new therapeutic peptides targeting a variety of diseases of bone and mineral ion physiology.
Thomas Gardella, Ph.D. is an Assistant Professor in Medicine and Biochemistry at the Massachusetts General Hospital and Harvard Medical School. He conducts laboratory research within the MGH Endocrine Unit, of which he has been a member since 1988.
Dr. Gardella’s research concerns the basic mechanisms by which peptide hormones interact with their cell-surface receptors, and specifically focuses on the parathyroid hormone (PTH) receptor. The PTH receptor is a G protein-coupled receptor that acts as a critical regulator of intracellular signaling processes involved in bone growth and blood calcium ion homeostasis. Alterations that perturb the PTH receptor cell signaling system are associated with a number of diseases of bone and mineral ion physiology. By dissecting the molecular mechanisms by which the PTH receptor functions, Dr. Gardella hopes to reveal clues that may help in the development of new therapies for such diseases, including Jansen’s chondrodysplasia, hypoparathyroidism and osteoporosis.